Certain bis-1, 1-dipyridyl olefins and therapeutically useful salts



.pounds with strong inorganic or organic acids.

CERTAIN BIS-1,1-DIPYRIDYL OLEFINS AND THERAPEUTICALLY USEFUL SALTS William Laszlo Bencze and Milton Joel Allen, Summit, N.J., assignors to Ciba Pharmaceutical Products, Inc., Summit, N.J., a corporation of New Jersey No Drawing. Application July 14, 1958 Serial No. 748,114

4 Claims. or. 260490 The present invention concerns pyridine compounds. More particularly, it relates to compounds of the formula:

C Ra RA in which each of the radicals R and R stand for 3-pyridyl or 4-pyridyl radicals and R and R for lower alkyl, the salts and quaternary ammonium compounds, as well as process for the preparation of such compounds.

The 3-pyridyl and the 4-pyridyl radicals are preferably unsubstituted or may contain lower alkyl radicals, e.g. methyl or ethyl, as substituents.

Salts of the new compounds of this invention are particularly therapeutically useful acid addition salts such as those with inorganic acids, for example, hydrohalic .acids, e.g. hydrochloric or hydrobromic acid; nitric or thiocyanic acid; or sulfuric or phosphoric acids; or those with organic acids, such as formic, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-arninobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, mandelic, salicylic, 4-aminosalicylic, Z-phenoxybenzoic, 2-acetoxybenzoic, methane sulfonic, ethane sulfonic, hydroxyethane sulfonic, benzene sulfonic, p-toluene sulfonic, naphthalene sulfonic or sulfanilic acid or methionine, tryptophane, lysine or arginine. Monoor bis-salts may be formed depending on the conditions used for the preparation of the salts.

Quaternary ammonium compounds are those formed with reactive esters of hydroxylated hydrocarbon com- Such esters are particularly lower alkyl halides, e.g. methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride or isopropyl bromide; lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane sulfonate or ethane sulfonate; di-lower alkyl sulfates, e.g. methyl or ethyl sulfate; or lower alkyl aryl sulfonate, e.g. methyl p-toluene sulfonate. Furthermore, quaternary ammonium hydroxides and the salts thereof with other acids, particularly with the organic acids outlined hereinabove as being suitable for the adrenal cortex, and, therefore, a remarkable inhibition of the production of adrenocortical hormones such as derivatives of l7a-hydroxy-pregnane, e.g. cortisone, without 'showing adverse secondary or essentially toxic effects.

They .are intended to be used as agents torelieve conditions which are known to be directly influenced by a hyperactivity of this vital gland, such as the Cushings syndrome or the adrenogenital syndrome. Furthermore,

2,923,716 Patented Feb. 2, 1960 ice in which R and R represent the 3-pyridyl or the 4-pyridyl radical, as well as the salts of these compounds. This group is represented by the compound of the formula:

and the salts with hydrohalic acids, e.g. hydrochloric acid, or with hydroxy carboxylic acids, e.g. tartaric acid.

The new pyridine compounds are also capable of reversing experimentally induced ascites in the dog in a dose of from about 1 to mg./kg. (parenterally), which results in an increased output of urine and sodium. Furthermore, the new pyridine derivatives may be used as diagnostic tools to define the pathogenic role of aldosterone in patients exhibiting sodium retention associated with increased urinary excretion of the steroid, and thus aid in predicting the results of adrenal surgery.

The new compounds may be used in the form of pharmaceutical preparations, which contain the new pyridine derivatives, salts or quaternary ammonium compounds thereof in admixture with a pharmaceutical organic or inorganic solid or liquid carrier suitable for enteral, e.g. oral, or parenteral administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly or any other known carrier for medicaments. The pharmaceutical preparations may be in solid form, for example, as tablets, dragees or capsules, or in liquid form, for example, as solutions or emulsions. If desired, they may contain auxiliary substances, such as preserving agents, stabilizing agents, salts for varying the osmotic pressure or buffers such as sodium metaphosphate. They may also contain, in combination, other therapeutically useful substances.

The new pyridine compounds of this invention may be prepared by dehydrating compounds of the formula:

Il a Rr-CH-O-RQ OH R4 -in which R R R and R have the above-given meaning, or salts thereof, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting compound into a salt or a quaternary ammonium compound thereof. The dehydration is carried outby treating the starting material or a salt, such as a hydrohalide, e.g. hydrochloride or hydrobromide, or a sulfate, thereof with a strong inorganic Lewis acid. Particularly suitable as a dehydration reagent is sulfuric acid, especially in its concentrated form. The reaction may be carried out at room temperature; however,.better yields are obtained by heating the reaction mixture from 3 .about 50 C. to about 200 C. The dehydration of the starting material of the formula:

Ira ru-oru-o-m OH R4 in which R R R and R have the above-given meaning, proceeds with a simultaneous rearrangement to the desired compounds of the formula:

Ra R4 The starting materials used in the above reaction are known. They may be prepared by rearranging diols of the formula:

OH OH in which R R and R and R have the above given meaning and either R or R stands also for CH -R in which R stands for hydrogen and lower alkyl, or a salt thereof in the presence of a strong Lewis acid, such as concentrated sulfuric acid, to form a mixture of the compounds of the formulae:

in which R R R and R have the above-given meaning, and in which R stands for hydrogen or lower alkyl, or the salts thereof. This mixture can be separated into the single compounds, for example, by fractionated distillation, fractionated crystallization, adsorption on an adsorbent, such as aluminum oxide and elution of the compounds with different solvents or solvent mixtures, or by conversion of the mixture into the mixture of functional ketone derivatives, e.g. oximes, separation of the mixture of the derivatives and conversion of the separated derivatives into the free ketones, for example, by treatment with an acid, e.g. aqueous sulfuric acid. Upon reduction, for example, by treatment with an alkali metal aluminum hydride, e.g. lithium aluminum hydride, in the presence of an ether solvent, e.g. diethyl ether or 'tetrahydrofurane, or by treatment with aluminum alkoxide, e.g. aluminum isopropyl-oxide, in the presence of a lower alkanol, e.g. isopropanol, the hydroxyl compounds of the formula:

i s R1(l3H-(|3R:

OH R4 in which R R R and K; have the above-given meaning, can be obtained. The free bases or the salts thereof are used .as the starting materials for the preparation .of the compounds of this invention.

The ketones of the formula:

in which R R R and R have the above-given meaning, and which are produced in the preparation of the starting materials of the compounds of this invention, can be likewise reduced to hydroxyl compounds of the formula:

in which R R R and R have the above-given meaning. These hydroxyl compounds or the salts thereof undergo dehydration without rearrangement when treated with a strong inorganic Lewis acid, such as concentrated sulfuric acid, to yield unsaturated pyridine compounds of the formula:

in which R R R and R have the above-given mean ing, and, if desired, a resulting salt can be converted to the free base, and/or, a resulting base can be converted into a salt or a quaternary ammonium compound thereof. The resulting pyridine compounds, their salts and quaternary ammonium compounds thereof also show an inhibitory effect on the activity of the adrenal cortex. They may be used in the same manner as the compounds described hereinbefore, for example, to relieve conditions directly influenced by a hyperactivity of the adrenal cortex, such as the Cushings syndrome or the adrenogenital syndrome and are therefore intended to be included within the scope of this invention.

The new compounds of this invention may be obtained in the form of the free bases or as the salts thereof. The salts may be converted into the free bases in the customary way, for example, by reaction with an aqueous alkaline reagent, such as an alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide; an alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate; or ammonia. The free bases may be transformed into their therapeutically useful acid addition salts by reaction with an inorganic or organic acid such as with one of the acids outlined above, for example, by treatment of a solution of the base in a lower alkanol, e.g. methanol, ethanol, propanol or isopropanol, with the appropriate acid or a solution thereof.

The new pyridine derivatives of this invention may be converted into the quaternary ammonium compounds by reacting the tertiary bases with an ester formed by a hydroxylated lower hydrocarbon compound with a strong inorganic or organic acid. Hydroxylated lower hydrocarbon compounds contain from one to sevencarbon atoms, and the esters thereof are more especially those with mineral acids, e.g. hydrochloric, hydrobromic, hydriodic, or sulfuric acid. Such esters are specifically lower alkyl halides, e.g. methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride or isopropyl bromide; lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate; di-lower alkyl sulfates, e.g. dimethyl or diethyl sulfate; or lower alkyl aryl sulfonates, e.g. methyl ptoluenesulfonate. The quaternizing reactions may be performed in the presence or absence of a solvent, under cooling, at room temperature or at an elevated temperature, at atmospheric pressure or in a closed vessel under pressure. Suitable solvents are more especially lower alkanols, e.g. methanol, ethanol, propanol, isopropanol, butanol or pentanol; lower alkanones, eg. acetone or ethyl methyl ketone; or organic acid amides, e.g. formamide or dimethylformamide.

' 1,1-bis-(3-pyridyl)-l-propene which crystallizes standing, and is recrystallized from a mixture of ethyl Resulting quaternary ammonium compounds may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting resulting quaternary ammonium halides, with silver oxide, by reacting quaternary ammonium sulfates with barium hydroxide, by

there may be formed therapeutically suitable quaternary ammonium salts by reaction with acids, such as with the inorganic and organic acids outlined hereinbefore as being useful for the formation of acid addition salts; or with mono-lower alkyl sulfates, such as methyl or ethyl sulfate. A quaternary ammonium compound obtained may also be converted directly into another quaternary ammonium salt without conversion into the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride, or the quaternary ammonium iodide may be converted into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol.

The invention also comprises any modification .of th general process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates. 7 The following examples illustrate the invention. They are not to be construed as limitations thereon. Temperatures are given in degrees centigrade.

Example 1 sulfate, filtrated and evaporated to dryness under reduced pressure. 6.6 g. of a gummy residue is distilled at 120- 130/ 0.05 mm. and yields 6.3 g. of the colorless Z-methylupon acetate and pentane, M.P. 142143.5.

The dihydrochloride is prepared by treating an ethanol solution of the free base with an ether solution of hydrogen chloride and adding additional ether.

By substituting 2-methyl-l,2-bis-(4-pyridyl)-propanol for the 2-methyl-1,2-bis(3-pyridyl)-propanol in the above reaction the Z-methyl-1,1-bis-(4-pyridyl)-1-propene may be prepared.

I Example 2 1.11 g. of 3,3-bis-(3-pyridyl)-2-butanol is dissolved in 5 ml. of concentrated sulfuric acid, and the mixture is kept at 7585 for four hours. It is then poured onto ice, the pH is adjusted 'to about 8, and extracted three times with ethyl acetate. The combined extracts are washed, dried, filtered and evaporated to dryness. The residual oil is distilled at 130-160/0.03 mm. and redis- Ltilled at 120-125/0.03 mm. to yield 0.34 g. of 3 ,3-bis(3- pyridyl)-1-butene, which may be identified as the dioxalate, prepared by treating an ethanol solution of the base with oxalic acid.

By using 4,4-bis-(3-pyridyl)-3-hexanol as the starting material in the above reaction the 4,4-bis-(3-pyridyl)-2- hexene may be obtained.

The starting materials used in the above examples may be prepared as follows:

A total amount of 300 g. of 2,3-bis-(3-pyridyl)-2,3-butanediol is added in to 20 g. portions to 1000 ml. of

concentrated sulfuric acid while stirring. During the addition the temperature is kept at 5 060 and is then raised to 75 at which temperature it is maintained for 7 hours and allowed to stand at room temperature for 12 hours. The sulfuric acid solutionis poured on ice and the pH brought to about 8 by addition of a 50% aqueous solution of sodium hydroxide; the temperature is kept below 50. The aqueous solution is extracted twice with ether and the ether solution is washed twice with a saturated aqueous solution of sodium chloride, then dried over sodium sulfate, and the ether evaporated to dryness under reduced pressure. 175 g. of the resulting residue is dissolved in a mixture of 50 ml. of ether and 50 ml. of pentane and cooled in the refrigerator. By keeping the solution in the cool overnight, 72 g. of the 2-methyl-1, 2-bis- (3-pyridyl)-propane-1-one is obtained and is recrystallized from a lzl-mixture of ether and pentane.

The mother liquor obtained from the crystallization step of the crude product with a mixture of ether and pentane contains, according to the infrared spectrum, an about lzl-mixture of the two ketone compounds and is worked up as follows: The solvents are distilled off and 45.4 g. of the resulting residue is dissolved in ethanol. A solution of g. of hydroxyl-amine sulfate in ml. of water, then a mixture of 80 g. of sodium acetate and 20 g. of sodium carbonate in 200 ml. of water are added in succession. After refluxing for 5 hours the ethanol is removed under reduced pressure and the pH adjusted to 8 by adding an aqueous solution of potassium carbonate. The aqueous solution is extracted three times with ethyl acetate, however part of the solid material cannot be dissolved and is filtered off. The ethyl acetate solution is dried over sodium sulfate and the solvent partially evaporated. The resulting precipitate is filtered off, and ether is added to the filtrate, whereupon 16 g. of a crystalline material is formed which is filtered off, and the filtrate is evaporated to dryness. The remaining viscous oil is dissolved in ethyl acetate, ether is added and 5.5 g. of

crystalline material precipitates which melts at 132137, and is redissolved in 70 ml. of ethyl acetate. The insoluble material is filtered off and the filtrate cooled to 4.2 of the oxime of 3,3-bis-(3-pyridyl)-butane-2- one precipitates, melting at 132-134.

1 g. of the oxime of 3,3-bis-(3-pyridyl)-butane-2-one is refluxed for 6 hours in 20 ml. of a 2 N aqueous solution of sulfuric acid and allowed to stand at room temperature overnight. The solution is made basic to pH 8 with a 10% aqueous solution of sodium hydroxide, then extracted three times with ether, which solution is then washed with a saturated aqueous solution of sodium chloride and dried over sodium carbonate. The ether is evaporated leaving 0.9 g. of a viscous oil, which does not respond to crystallization upon seeding with crystalline Z-methyl-1,2-bis-(3-pyridyl)-propane-1-one previously obtained. It is distilled, B.P. 135/0.05 mm., and the distillation is stopped after one third of the original amount is collected; infrared studies of this material show a uniform compound containing an unco'njugated carbonyl group.

The distillate is dissolved in a lzl-mixture of water and concentrated hydrobromic acid, the water is evaporated under reduced pressure and the residue is triturated with a mixture of methanol and ether; the crystalline material is filtered off and recrystallized from the same mixture. The resulting dihydrobromide of the 3,3-bis-(3-pyridyl)- butane2-one melts at 240-243 and gives a melting point depression with a sample of the dihydrobromide of 2- methyl-l,2-bis-(3-pyridyl)-propane-l-one to be described hereinafter.

A solution of the dihydrobromide of 3,3-bis-(3- pyridyl)-butane-2-one in water is adjusted to pH 8 with a 2 N aqueous solution of sodium hydroxide, the solution extracted with ethyl acetate which solution is dried and I '3' pyridyl)-butane-2-one, Ml. 47-49. A mixture with 2- methyl-1,2bis-(3-pyridyl)-propane-2-one previously obtained melts at room temperature.

The lzl-rnixture of the two ketones one of which contains a conjugated carbonyl group, the other an unconjugated carbonyl group, obtained after the crystallization of the reaction mixture from ether and pentane, may also be separated into the two constituents as follows: 5.7 g. of said mixture in ml. of benzene is placed on a column containing 250 g. of aluminum oxide (basic, activity 111) which has been washed with hexane. The lzl-mixture fraction of hexane and benzene and the benzene fraction contain a total of 1.64 g. of crystalline 2-methyl-1,2-bis- (B-pyridyl)-propane-l-one, the ether fraction 2.10 g. of the oily 3,3-bis-(3-pyridyl)-butane-2-one.

The 2'methyl-1,2-bis-(3-pyridyl)-propanol used in Example 1 may be prepared as follows: A solution of 6.42 g. of 2-methyl-1,2-bis-(3-pyridyl)-propane-1-one in 25 ml. of ether is slowly added to a boiling suspension of 1.08 g. of lithium aluminum hydride in 50 ml. of ether, and the mixture is refluxed for 8 hours. The excess of lithium aluminum hydride is carefully destroyed with water and a 6 N aqueous solution of hydrogen chloride is added to dissolve the precipitate. The aqueous solution is adjusted to pH 8 with a 2 N aqueous solution of sodium hydroxide and then twice extracted with ethyl acetate; the latter solution is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The organic solvent is evaporated and 6.0 g. of the remaining viscous oil is distilled, B.P. 130-150/0.05 mm. Upon standing, the oil crystallizes and is recrystallized from a mixture of ethyl acetate and pentane to yield the Z-methyll,2-bis-(3-pyridyl)-propanol, Ml 104105.

The 3,3-bis-(3-pyridyl)-2-butanol used in Example 2 may be prepared as follows: By treating 6.1 g. of 3,3-bis- (3-pyridyl)-butane-2-one with 2.0 g. of lithium aluminum hydride as previously described, 5.7 g. of crystalline material is obtained from the ethyl acetate extraction which after crystallization from a mixture of ethanol, ether and pentane, and distillation yields the 3,3-bis-(3-pyridyl)-2- butanol, B.P. 140/01 mm. and melts at 165-166".

The compounds of the formula:

in which R R R and R have the above-given meaning, may also be prepared by reacting a compound of the formula:

with a R (R )CH-metal, a [R (R )CH] -metal or a R (R )CH-metal halide compound according to the Grignard procedure and, if necessary, dehydrating the resulting hydroxyl compound, and, if desired, converting a resulting salt into a free compound, and/or, if desired, converting a free compound into a salt or a quaternary ammonium compound. The metals used in the above reagents are particularly metals of lower molecular weight selected from group IA of the periodic system, e.g. lithium, bivalent metals of lower molecular weight selected from the group HA of the periodic system, e.g. magnesium, or bivalent metals selected from group HB of the 3 periodic system, e.g. zinc or cadmium; halide anions are particularly chlorine, bromine or iodine anions. The reaction is carried out in the presence of an inert solvent, such as an ether, e.g. diethyl ether, diethylene glycol dimethylether, anisole, tetrahydrofurane or dioxane; or an aromatic hydrocarbon, e.g. benzene, toluene or xylene. Dehydration of any resulting hydroxyl compound may be accomplished by distillation, or, more preferably, by treatment with an acid, such as a strong inorganic acid, for example, a mineral acid, e.g. hydrochloric, hydrobromic or sulfuric acid. The following example illustrates this reaction.

Example 3 0.1 mol of di-(3-pyridyl)-ketone is dissolved in dry ether and added dropwise to a refluxing ether solution of 0.1 mol of isopropyl magnesium chloride. After refluxing for 8 hours, the magnesium complex is destroyed by adding a 2 N aqueous solution of hydrochloric acid. The acidic solution is separated from the ether layer and extracted once with ether. The aqueous solution is rendered slightly basic wtih aqueous ammonia and then extracted three times with methylene chloride. The combined organic extracts are dried and evaporated to dryness and the residue is distilled. To dehydrate any 2-methyl- 1,l-bis-(3-pyridyl)wpropanol present, the distillate is treated with concentrated sulfuric acid, the acid solution is poured on ice, rendered basic with aqueous ammonia and then extracted with ether. The ether extract yields the desired 2-methy1-1,l-bis (3-pyridyl)-1-propene after drying, evaporation and distillation of the residue according to the procedure of Example 1.

What is claimed is:

1. Amemberof the group consisting of compounds of the formulae:

in which each of the radicals R and R stands for a member of the group consisting of 3-pyridyl and 4-pyridyl, each of the radicals R and R stands for lower alkyl, and R represents a member of the group consisting'of hydrogen and lower alkyl, and the therapeutically useful acid addition salts thereof.

2. 2-methyl-1,1-bis( 3-pyridyl) -1-propene.

3. 2-methyl-1,1-bis-(4-pyridyl)-1-propene.

4. 3 ,3 -bis-( 3-pyridyl) -1-butene.

References Cited in the file of this patent UNITED STATES PATENTS 2,534,285 Mahan Dec. 19, 1950 2,556,845 Kaufmann June 12, 1951 2,698,848 Mahan Jan. 4, 1955 2,749,349 Cislak June 5, 1956 2,754,300 MacLean et a1. July 10, 1956 OTHER REFERENCES .Bergmann et al.: Chem. Abstracts, vol. 48, col. 2708 (1954).

Beyermann et al.: Chem. Abstracts, vol. 50, col. 10719 (1956). 

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAE: 